The hippocampus is critical for the formation and consolidation of spatial memories and contributes to other cognitive tasks through its efferent projections. The goal of this project is to determine whether altered neuronal network activity in the hippocampus of an autism mouse model propagates to, and alters distal cortical regions involved in social behaviors. One of the core symptoms of autism spectrum disorders, such as Rett syndrome (RTT), is a deficit in social interaction. In mice, similar social behavior impairments can be modeled by altering the excitation and inhibition (E/I) balance in the medial prefrontal cortex (mPFC). For RTT, knocking out the gene that is mutated in humans, Mecp2, causes hyperactivity in the ventral hippocampus (vHIP) due to an E/I imbalance driven by impaired inhibition and enhanced excitation, resulting in saturated synaptic plasticity at excitatory synapses. Intriguingly, CA1 pyramidal neurons of the vHIP project their axons to the mPFC, making direct monosynaptic connections with excitatory pyramidal neurons and inhibitory interneurons. We propose to characterize how the vHIP influences mPFC activity through this long-range monosynaptic glutamatergic projection. Importantly, we will test whether altered vHIP network activity is causal to mPFC dysfunction and deficits in social interaction. We hypothesize that atypically strong vHIP afferents alter network activity in the mPFC of Mecp2 KO mice by affecting the E/I balance and synaptic plasticity, which in turn contributes to social interaction deficits. To test this hypothesis, we will identify the cellular targets of direct vHIP afferents in the mPFC of RTT mice and characterize their function in social behaviors using a combination of optogenetics, chemogenetics, ex vivo and in vivo electrophysiology and Ca2+ imaging, anterograde and retrograde tract tracing, and unbiased machine-learning behavioral assessments. We propose the following Specific Aims: 1) identify and characterize the cellular targets of the monosynaptic projection from the vHIP to the mPFC in Mecp2 KO mice; 2) characterize long-term synaptic plasticity of the vHIP-mPFC projection in Mecp2 KO mice; and 3) determine if chemogenetic modulation of the activity of mPFC-projecting vHIP neurons alters mPFC function and social behaviors. These studies will provide fundamental information on the functional and structural properties of the long- range connection between the vHIP and mPFC in the developing brain. The impact of this work extends beyond RTT to other neuropsychiatric disorders in which propagation of network dysfunction from the hippocampus to the mPFC is believed to contribute to cognitive deficits.